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PubMed1993

Activation of recombinant murine cytotoxic cell proteinase-1 requires deletion of an amino-terminal dipeptide.

Murine cytotoxic cell proteinase-1 (granzyme B) is a member of a family of novel serine proteinases that have been implicated to participate in destruction of target cells by cytotoxic T lymphocytes. Comparison of the sequence of the cDNA with the sequence of the protein isolated from cytoplasmic granules of cytotoxic T lymphocytes suggested that this protein may be synthesized as a preproenzyme containing an amino-terminal activation dipeptide. Here we show that this activation dipeptide regulates the activity of the enzyme in hydrolysis of its preferred substrate tert-butyloxycarbonyl-Ala-Ala-Asp-thiobenzyl ester. Lysates of COS cells transfected with a vector expressing the unmodified cytotoxic cell proteinase-1 cDNA were unable to hydrolyze this substrate, whereas lysates of cells transfected with a construct in which the activation dipeptide codons has been deleted were able to hydrolyze the substrate. In each case Western blotting of the lysates revealed a form of the proteinase with an apparent molecular weight of 27,000. We conclude that the activation dipeptide regulates activity of the enzyme. This is the first report of production of an enzymatically active recombinant cytotoxic T cell serine proteinase. The strategy for successful expression of an activated form of cytotoxic cell proteinase-1 may be applicable to other members of this proteinase family.

Amino Acid Sequence↗
PubMed1997

[Conformational states of cyclic dipeptides with lactam bond between omega-functions of lysine and aspartic or glutamic acid residues].

The conformations of H-Lys-Asp-OH and H-Glu-Lys-OH cyclic dipeptides were subjected to theoretical analysis by the method of atom-atom potentials with flexible geometry. Constants of spin-spin coupling of vicinal protons were calculated for the theoretical conformers of both dipeptides. CD and NMR spectra were measured for both peptides synthesized, and the calculated and experimental values of spin-spin coupling constants were compared. These coincided well for the dipeptide containing Asp residue, and we concluded that it exists in solution as one conformer. For the Glu-containing dipeptide, the existence of minor conformers, which increase the difference between experimental and theoretical spin-spin coupling constants, was shown to be possible.

Aspartic Acid↗
PubMed1986

Muramyl dipeptide enhances survival from experimental peritonitis.

Muramyl dipeptide is a nonspecific immunostimulant derived from Freund's complete adjuvant. We determined the effect of muramyl dipeptide on two separate animal models for peritonitis. We found that administration of muramyl dipeptide to rats undergoing cecal ligation and puncture significantly reduced mortality. Similarly, mice that underwent cecal ligation alone with muramyl dipeptide administration also had a statistically significant reduction in mortality compared with untreated controls.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1990

Catabolic effects of muramyl dipeptide on rabbit chondrocytes.

Muramyl dipeptide, an essential structure for the diverse biologic activities of bacterial cell wall peptidoglycan, inhibited the synthesis of glycosaminoglycan/proteoglycan in cultured rabbit costal chondrocytes in a dose-dependent manner. Muramyl dipeptide, as well as lipopolysaccharide and interleukin-1 alpha, also enhanced the release of 35S-sulfate-prelabeled glycosaminoglycan/proteoglycan from the cell layer, which seems to reflect, at least partially, the increasing degradation of glycosaminoglycan/proteoglycan. Five synthetic analogs of muramyl dipeptide known to be adjuvant active or adjuvant inactive were tested for their potential to inhibit synthesis of glycosaminoglycan/proteoglycan and to enhance the release of glycosaminoglycan/proteoglycan in chondrocytes. The structural dependence of these synthetic analogs on chondrocytes was found to parallel that of immunoadjuvant activity. These results suggest that muramyl dipeptide is a potent mediator of catabolism in chondrocytes.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2002

Effects of nitric oxide synthase inhibitors on the febrile response to muramyl dipeptide and lipopolysaccharide in rats.

We have administered aminoguanidine, a relatively specific inhibitor of inducible nitric oxide synthase, and N-nitro-L-arginine methyl ester (L-NAME), an unspecific nitric oxide synthase inhibitor, to rats made febrile with the gram-positive pyrogen, muramyl dipeptide and gram-negative pyrogen, lipopolysaccharide. Sprague-Dawley rats, housed individually at approximately 25 degrees C with a 12:12 h light:dark cycle (lights on 0700 hours), were injected (at 0900 hours) intraperitoneally with 50 mg/kg aminoguanidine, 25 mg/kg or 50 mg/kg L-NAME, and intramuscularly with 500 microg/kg muramyl dipeptide or 100 microg/kg lipopolysaccharide. Pyrogen injections were spaced at least 14 days apart. Body temperature was measured throughout the study in unrestrained animals using radio-telemetry. Neither muramyl dipeptide nor lipopolysaccharide-induced fevers were affected by aminoguanidine. However, L-NAME administration inhibited muramyl dipeptide and lipopolysaccharide-induced fevers, but only for the 1st 2-4 h of the fevers (two-way ANOVA, P<0.05). After the initial inhibition, lipopolysaccharide fevers developed normally. Therefore, constitutively expressed nitric oxide synthase appears to be involved in the initial phases of fever genesis of gram-negative and gram-positive fevers in rats. On the other hand, inducible nitric oxide synthase appears not to play a role in these fevers.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMedDate not supplied

A comparison of the antinociceptive and behavioral effects of D-Arg substituted dipeptides and tetrapeptides in mice.

Intracerebroventricular administration of D-Arg substituted dipeptides, H-Tyr-D-Arg-OMe and H-Tyr(Et)-D-Arg-OMe, and D-Arg2 substituted N-terminal tetrapeptides of dermorphin, H-Tyr-D-Arg-Phe-Gly-OEt and H-Tyr(Et)-D-Arg-Phe-Gly-OEt resulted in dose-related and naloxone-reversible antinociceptive effects. Among them, tetrapeptides not only exhibited much more potent and prolonged activities than dipeptides but also were significantly antagonized even by a low dose of naloxone. Spontaneous motor activity was lowered by dipeptides throughout the observation period, which was scarcely antagonized by naloxone. Tetrapeptides elicited locomotor hyperactivity following an initial locomotor suppression. Only the locomotor hyperactivity was significantly antagonized by naloxone. These results suggest that tetrapeptides induce the effects via opioid receptors, whereas the effects of dipeptides are involved in various systems non-specifically.

Animals↗
PubMed1996

Dipeptide-derived diphenyl phosphonate esters: mechanism-based inhibitors of dipeptidyl peptidase IV.

A number of dipeptide diphenyl phosphonate esters were studied as inhibitors of dipeptidyl peptidase IV, focusing on the role of the P2 residue in the inactivation process. The active compounds were slow irreversible inhibitors of the catalytic activity of the enzyme. With proline (or alanine) in the P1 position, the rate constants of inactivation correlated with the acylation rate constants reported for homologous dipeptide derived substrates. The kinetic data indicate that the mechanism of inhibition consists of the formation of a fairly weak initial complex, followed by a slow irreversible inactivation step. This indicates that, as in the case of trypsin-like proteinases, dipeptide diphenyl phosphonate esters form a covalent adduct with the catalytic site of DPP IV, even though this enzyme belongs to a completely distinct class of serine peptidases. Enantioselectivity and secondary specificity further support the evidence that diphenyl phosphonate esters are mechanism-based inhibitors. The dipeptide diphenyl phosphonate esters had a half-life of 3-10 h at 37 degrees C in Tris buffer. The inhibitors were degraded in human plasma, depending on the type of amino-terminal amino acid. The compound with proline in the P2 position was the most resistant to degradation in plasma. Due to their stability and the irreversible nature of the inhibition, the diphenyl phosphonate esters promise to be useful tools in the continuing investigation of the physiological function of dipeptidyl peptidase IV.

Binding Sites↗
PubMed2004

Modulation of cytokine production by some phthalimido-desmuramyl dipeptides and their cytotoxicity.

Muramyl dipeptide (MDP) is the smallest bacterial cell wall peptidoglycan component having immunomodulatory activity. In an attempt to obtain MDP derivatives with improved and better defined pharmacological profiles we synthesized a new lipophilic phthalimido-desmuramyl dipeptide, LK 508. This novel MDP analogue and three structurally related phthalimido-desmuramyl dipeptides (LK 413, LK 511 and LK 512) were evaluated immunologically. Their ability to modulate the production of cytokines was measured in vitro by their inclusion in cultures of human peripheral blood mononuclear cells (PBMC) activated by ionomycin and phorbol-12-myristate-13-acetate (PMA). The results were compared with the analogous activity of MDP. All compounds tested are strong up-regulators of IL-12 synthesis. All compounds except LK 512 also stimulated IFNgamma synthesis. LK 508, LK 511 and LK 512 are effective in up-regulating IL-2 production. LK 508 and LK 512 considerably up-regulate the synthesis of IL-4 and IL-10. LK 413 and MDP stimulated the production of Th1 promoting and Th1 (IFNgamma and IL-12) cytokines, while LK 508, LK 511 and LK 512 non-selectively up-regulated the production of both Th1 and Th2-types of (IL-4 and IL-10) cytokines. None of the phthalimido-desmuramyl dipeptides was cytotoxic in vitro against the normal cell line HUVEC (human endothelial cells) thereby indicating their potential for use in vivo.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2004

Cyclic dipeptides exhibit synergistic, broad spectrum antimicrobial effects and have anti-mutagenic properties.

Cyclic dipeptides are known to have antiviral, antibiotic and antitumour properties. The aim of this study was to determine the combined effects of cyclo(L-leucyl-L-prolyl) and cyclo(L-phenylalanyl-L-prolyl) on the growth of vancomycin-resistant enterococci (VRE) and pathogenic yeasts, as well as determining their anti-mutagenic effects. This drug combination was especially effective against five VRE strains: Enterococcus faecium (K-99-38), E. faecalis (K-99-17), E. faecalis (K-99-258), E. faecium (K-01-312) and E. faecalis (K-01-511) with MIC values of 0.25-1 mg/l. It was also effective against Escherichia coli, Staphylococcus aureus, Micrococcus luteus, Candida albicans and Cryptococcus neoformans with MIC values of 0.25-0.5 mg/l. In addition, the cyclic dipeptides exerted anti-mutagenic activity against Salmonella typhimurium TA98 and TA100 strains in a Salmonella mutation assay. The number of mutant colonies of S. typhimurium strains TA98 and TA100 induced by exposure to AF-2 (0.2 microg/plate) decreased in a concentration-dependent manner in the presence of the two cyclic dipeptides (correlation 0.72 and 0.78, respectively). Here, for the first time, we report synergistic effects of the cyclic dipeptides [cyclo(L-leu-L-pro) and cyclo(L-phe-L-pro)] in inhibiting the growth of pathogenic microorganisms, as well as their anti-mutagenic effects in Salmonella strains.

Anti-Bacterial Agents↗
PubMed1997

Influence of a novel amino acid solution (enriched with the dipeptide glycyl-tyrosine) on plasma amino acid concentration of patients with acute renal failure.

In this randomized, double-blind controlled study we compared the effect of parenteralnutrition with two different amino acid solutions on the plasma concentration of amino acids in 27 patients with acute renal failure. Fourteen patients received the new dipeptide-containing (glycyl-tyrosine) amino acid solution (AADI) in combination with glucose (60%) and fat (10%) as an 'all-in-one' solution over 120 h continuously via a central venous catheter. In the control group (AAST), parenteral nutrition with a standard amino acid solution in isonitrogenous and isocaloric form (0.7 g amino acids/kg BW/day and 25 kcal/kg BW/day) was administered to 13 patients over the same period of time. The administration of the dipeptide-containing amino acid solution caused a return to within the normal range of most of the amino acid concentrations which were decreased at the onset. A significant difference could be found between the AADI and AAST group for the achieved plasma concentrations of threonine (P < 0.01), phenylalanine (P<0.05), isoleucine (P<0.05), tryptophan (P<0.01) and ornithine (P<0.05), The phenylalanine/tyrosine ratio, did not change in the AADI group, while a marked increase was observed in the AAST group. (152.7 +/- 23.5 - 159.8 +/- 37.6 vs 172.6 +/- 24.6 - 310.6 +/- 136.7, respectively). The plasma concentration of glycyl-tyrosine was at the limit of detectability indicating rapid hydrolysis of the dipeptide in acute renal failure. These data suggest that the new dipeptide-containing amino acid solution offers a clear advantage over a standard amino acid formulation in correcting the amino acid imbalances in plasma of patients with ARF and is able to maintain normal tyrosine concentrations and phenylalanine/tyrosine ratio.

Journal Article↗
PubMedDate not supplied

In vivo ocular pharmacokinetics of acyclovir dipeptide ester prodrugs by microdialysis in rabbits.

In vivo corneal absorption of the dipeptide prodrugs of acyclovir (ACV) was evaluated using microdialysis in rabbits. A corneal well was placed on the cornea of the anesthetized New Zealand White rabbits with implanted linear probes into the aqueous humor. Two hundred microliters of a 1% solution of L-valine-ACV (VACV), glycine-valine-ACV (GVACV), valine-valine-ACV (VVACV), and valine-tyrosine-ACV (VYACV) was placed in the corneal well and was allowed to diffuse for a period of 2 h, following which the drug solution was aspirated and well removed. Samples were collected every 20 min throughout the infusion and postinfusion phases and were analyzed by HPLC to obtain the aqueous humor concentrations. Absorption rate constants of all the compounds were found to be lower than the elimination rate constants. GVACV exhibited highest absorption rate (ka) compared with other prodrugs, but all the prodrugs showed similar terminal elimination rate (lambda(z)). The time of maximum absorption (Tmax) of ACV after administration of VACV and the dipeptide prodrugs did not vary significantly (p < 0.05). GVACV exhibited the highest concentration (Cmax) and area under curve (AUC) upon absorption (p < 0.05) compared to VACV, VVACV, and VYACV. Dipeptide prodrugs of ACV were absorbed through the cornea at similar rates but to varying extents. The dipeptide prodrug GVACV owing to its enhanced absorption of ACV seems to be a promising candidate for the treatment of ocular HSV infections.

Absorption↗
PubMed2003

Inhibition of intestinal dipeptide transport by the neuropeptide VIP is an anti-absorptive effect via the VPAC1 receptor in a human enterocyte-like cell line (Caco-2).

1. Optimal dipeptide and peptidomimetic drug transport across the intestinal mucosal surface is dependent upon the co-operative functional activity of the di/tripeptide transporter hPepT1 and the Na(+)/H(+) exchanger NHE3. The ability of the anti-absorptive enteric neuropeptide VIP (vasoactive intestinal peptide) to modulate dipeptide uptake was determined using human intestinal (Caco-2) epithelial cell monolayers. 2. Uptake of glycylsarcosine (Gly-Sar) across the apical membrane of Caco-2 cell monolayers is inhibited by basolateral exposure to either VIP, pituitary adenylate cyclase-activating polypeptide (PACAP), or the VPAC(1) receptor agonist [(11,22,28)Ala]-VIP. Inhibition of Gly-Sar uptake is observed only in the presence of extracellular Na(+). Reverse-transcription polymerase chain reaction (RT-PCR) demonstrates that VPAC(1) mRNA is expressed in Caco-2 cells whereas VPAC(2) mRNA is not detected. 3. The VIP-induced inhibition of Gly-Sar uptake is abolished in the presence of the protein kinase A (PKA) inhibitor H-89 (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide.2HCl). 4. (22)Na(+) uptake across the apical membrane is inhibited by the selective NHE3 inhibitor S1611. Experiments with BCECF [2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein]-loaded Caco-2 cells demonstrate that VIP reduces the NHE3-dependent recovery of intracellular pH (pH(i)) after dipeptide-induced acidification. Western blot of Caco-2 cell protein demonstrates expression of the NHE regulatory factor NHERF1 (expression of which is thought to be required for PKA-mediated inhibition of NHE3). 5. VIP has no effect on Gly-Sar uptake in the presence of S1611 suggesting that VIP and S1611 both modulate dipeptide uptake via the same mechanism. 6. These observations demonstrate that VIP (and PACAP) modulate activity of the H(+)/dipeptide transporter hPepT1 in a Na(+)-dependent manner consistent with the modulation being indirect through inhibition of NHE3.

Biological Transport↗
PubMed1969

The influence of short-range interactions on protein conformation. 3. Dipeptide distributions in proteins of known sequence and structure.

A statistical analysis is made of the distribution into alpha-helical and non-alpha-helical regions of the various dipeptide types appearing in a sample of seven proteins of known sequence and structure. By considering as a group all dipeptide types occurring at a given location relative to the reported helix-coil boundaries and examining the percentage of cases in which these appear in non-alpha-helical regions throughout the protein sample, we find a sharp change in the nature of the observed dipeptide types when the helix-coil boundary is crossed. Furthermore, we find that dipeptide types which occur in the coil region near the C-terminal end of helical segments are non-alpha-helical in almost 90 per cent of the cases in which they appear throughout the sample. No similar effect is found in the coil region near the N-terminal end of helical segments. These results give evidence for the importance of short-range interactions in determining protein conformation. They are also consistent with predictions based on a model for helix formation given in the second paper of this series.(1)

Amino Acid Sequence↗
PubMed1996

Role of hydrophobic substituents in the interaction of opioid Tyr-Tic dipeptide analogs with dodecylphosphocholine micelles. Molecular partitioning in model membrane systems.

The conformational properties of three Tyr-Tic-NH-R dipeptide analogs [where R = (CH2)2-Ph, (CH2)3-Ph or (CH2)2-cHx; Ph = phenyl; cHx = cyclohexyl and Tic = tetrahydroisoquinoline-3-carboxylic acid] have been investigated in purely aqueous solution and in the presence of fully deuterated dodecylphosphocholine micelles. H-Tyr-Tic-NH-(CH2)2-Ph is an opioid delta-agonist, whereas H-Tyr-Tic-NH-(CH2)3-Ph is a fairly potent delta-antagonist. H-Tyr-Tic-NH-(CH2)2-cHx is a less potent delta-antagonist. 1H-NMR spectra revealed that conformers containing cis and trans configurations of the Tyr-Tic peptide bond were present in all compounds in H2O and the H2O/lipid solvent. Analyses of the NMR data for the compounds in H2O indicate that in all three dipeptides the C-terminal substituent is flexible and the Tyr-side-chain adopts a trans orientation in most of the conformations. This promotes a compact Tyr-Tic structure. NOE patterns observed for the compounds in the micelle solution indicate that Tyr has an even greater tendency to assume a trans side chain configuration in the biphasic-solvent system. This feature was more pronounced in the trans conformers than in the cis conformers. Specific lipid-peptide interactions were indicated by NOESY spectra acquired for micelle samples incorporating 20% (by mass) protonated lipid. According to the obtained NOE data, Tyr and Tic form an aromatic cluster which preferentially inserts into the lipid interior of the micelle for the trans conformers of all three dipeptides and for the cis conformer of H-Tyr-Tic-NH-(CH2)2-Ph. For the cis isomers, partitioning of the C-terminal substituents into the lipid phase exhibited more diverse behaviour. The cis conformers of H-Tyr-Tic-NH-(CH2)3-Ph and H-Tyr-Tic-NH-(CH2)2-cHx preferentially anchor to the micelle via their C-terminal substituent, while the corresponding region in H-Tyr-Tic-NH-(CH2)2-Ph remains flexible and immersed in the aqueous phase. The inconsistent mode of peptide-micelle interaction observed for cis conformers of the three compounds studied is explained in terms of differences in their dipeptide-substituent hydrophobicities. The more apolar the substituent, the greater its tendency to preferentially insert into the lipid core of the micelle. Amide-proton temperature coefficients measured for the three peptides revealed differences amongst the cis and trans isomers. The amide proton in the trans conformer of each compound is highly exposed to the aqueous phase in both solvent systems studied, whereas the cis NH proton of each peptide is only partially exposed. These results demonstrate that a subtle structural modification of an active peptide analog can result in dramatic changes of its biological activity and its mode of partitioning at a membrane surface.

Amides↗
PubMed1979

Adjuvant activities in production of reaginic antibody by bacterial cell wall peptidoglycan or synthetic N-acetylmuramyl dipeptides in mice.

This paper is concerned with the adjuvant activity in stimulatory immunoglobulin E production against ovalbumin (OA) by bacterial cell walls, cell wall peptidoglycan (PG), and their PG fragments and synthetic N-acetylmuramyl (MurNAc) dipeptides in A/J mice. A PG isolated from Streptococcus pyogenes, PG subunit polymer and dimer obtained from Staphylococcus epidermidis, and water-soluble fragments of cell walls or PG prepared from Nocardia corynebacteriodes and Streptomyces gardneri were found to enhance both the primary and secondary responses of anti-OA immunoglobulin E antibody production. It was suggested that the PG portion, either intact or highly degraded, was capable of enhancing the immunoglobulin E antibody production, and there was no need for the non-PG moiety or intactness of PG structure for the adjuvant activity. This finding was confirmed and extended by the use of synthetic MurNAc dipeptides. Among eight MurNAc dipeptides tested, MurNAc-l-Ala-d-isoGln, MurNAc-l-Ala-d-Gln, MurNAc-l-Ala-d-Glu, and MurNAc-l-Ser-d-isoGln were found active as an adjuvant in the stimulation of the primary and secondary reaginic anti-OA antibody production in a similar way to the cell wall PG and their fragments. None of the synthetic MurNAc-l-Ala-l-isoGln, MurNAc-l-Ala-l-Gln, MurNAc-l-Ala-l-Glu, and MurNAc-l-Ala-d-isoAsn, on the other hand, stimulated the anti-OA immunoglobulin E antibody production in either primary or secondary response, indicating the importance for the adjuvancy in immunoglobulin E production of the configuration of the glutamic acid residues adjacent to the l-Ala (or l-Ser) in muramyl dipeptides.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1981

Effects of muramyl dipeptide treatment on resistance to infection with Toxoplasma gondii in mice.

Studies were carried out to determine whether treatment of mice with the synthetic adjuvant muramyl dipeptide afforded any resistance to infection with the obligate intracellular protozoan Toxoplasma gondii. Marked resistance to lethal challenge infection was observed in CBA but not C57BL/6 mice pretreated with muramyl dipeptide. In CBA mice, a single muramyl dipeptide treatment administered 14, 7, or 4 days before Toxoplasma challenge did not afford protection, whereas mice treated at -1 day were highly resistant. Additional studies carried out to investigate the mechanisms underlying the enhanced resistance to Toxoplasma in muramyl dipeptide-treated mice failed to reveal either enhanced cytolytic antibodies to the parasite or evidence that peritoneal macrophages from treated mice were activated as determined in vitro by their microbicidal capacity for Toxoplasma or cytotoxic capacity for tumor target cells.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1991

Identification and characterization of dppA, an Escherichia coli gene encoding a periplasmic dipeptide transport protein.

We describe the isolation and analysis of an Escherichia coli gene, dppA, and its role in dipeptide transport. dppA maps near min 79 and encodes a protein (DppA) that has regions of amino acid similarity with a peptide-binding protein from Salmonella typhimurium (OppA). Like OppA, DppA is found in the periplasmic space and thus is most likely a dipeptide-binding protein. Insertional inactivation of dppA results in the inability of a proline auxotroph to utilize Pro-Gly as a proline source. dppA-dependent Pro-Gly utilization does not require any of the three major proline transport systems, demonstrating that DppA is not simply a dipeptidase. An in vivo competition assay was used to show that DppA is probably involved in the transport of dipeptides other than Pro-Gly. Transcription of dppA is repressed by the presence of casamino acids, suggesting that the cell alters its dipeptide transport capabilities in response to an environmental signal.

Amino Acid Sequence↗
PubMed1985

[Muramyl dipeptide and its synthetic analog as possible inducers of interleukin-2 production].

Muramyl dipeptide and its synthetic derivative N-acetyl-glucosaminyl-N-acetyl-muramyl-alanyl - D-isoglutamine induce mitogenic factor production for Con A activated blasts (Con A-blasts) in splenocytes. The maximal factor production was revealed 24 h after stimulation with muramyl dipeptide or its derivative. Addition of the inducers to the culture of Con A-blasts led but to the negligible proliferative response. Therefore, the mitogenic action of muramyl dipeptide on target cells is mediated by the growth factor, evidently by interleukin-2. It has been also shown that muramyl dipeptide and its derivative with Con A exerted a synergic action in interleukin-2 induction.

Acetylmuramyl-Alanyl-Isoglutamine↗